The overall structure and function of the central nervous system is established via a variety of carefully orchestrated processes, including the formation of synapses and the morphogenesis of the dendritic arborization of individual neurons. These processes are subject to influence by external factors, including the changes in neuronal activity that occur in response to the administration of drugs such as cocaine, amphetamines, nicotine, and opiates. Recently, the small GTPase Rem2 was identified as a novel regulator of excitatory synapse development, dendritic spine formation, and dendritic arbor morphology. Additionally, the ability of Rem2 to mediate dendritic morphology is dependent on Rem2 binding to calmodulin (CaM). Interestingly, Rem2 is upregulated at the transcriptional level in response to neuronal depolarization, suggesting that it can act as a direc link by which a neuron can respond to changes in activity by altering its structure and function as needed. This proposal seeks to explore the signaling mechanisms through which Rem2 mediates dendritic arborization in response to changes in neuronal activity both in vitro and in vivo. Specifically, an in vitro system of cultured rodent hippocampal neurons will be used to explore the interaction of Rem2 with CaM kinase II, as existing data suggests that Rem2 is downstream of this known regulator of dendritic morphology. To explore the role of Rem2 in such activity-dependent changes in morphology in vivo, the optic tectum of Xenopus laevis tadpoles, a well-characterized experimental system, will be used to identify how Rem2 participates in the morphological changes caused by activity in the form of visual sensory experience. Importantly, Rem2 is expressed in the striatum, which is the site of action of the reward attributes associated with drug addiction, as well as the hippocampus, which has been shown to undergo structural changes in response to amphetamines. Changes in CaM kinase signaling have also been extensively implicated in opiate addiction. Thus, a comprehensive study of the signaling pathways in which Rem2 is involved will provide new insights into how the underlying structure of the brain is altered to produce the functional changes associated with drug use and addiction. Ultimately, Rem2 may represent a key molecule through which external stimuli mediate direct effects on those signaling pathways that regulate the structure of individual neurons and the central nervous system as a whole.